Real-life efficacy and safety of Ustekinumab as second- or third-line therapy in Crohn's disease: results from a large Italian cohort study.

OBJECTIVE: Ustekinumab (UST) is an anti-IL12/23 antibody for the treatment of Crohn's Disease (CD). The aim of this study was to compare the efficacy and safety of UST in a large population-based cohort of CD patients who failed previous treatment with other biologics. PATIENTS AND METHODS: 194 CD patients (108 males and 86 females, mean age 48 years (range 38-58 years) were retrospectively reviewed. 147 patients were already treated with anti-TNFα (75.8%), and 47 (24.2%) patients were already treated with anti-TNFα and vedolizumab. Concomitant treatment with steroids was present in 177 (91.2%) patients. RESULTS: At week 12, clinical remission was achieved in 146 (75.2%) patients. After a mean follow-up of 6 months, clinical remission was maintained in 135 (69.6%) patients; at that time, mucosal healing was assessed in 62 (31.9%) patients, and it was achieved in 33 (53.2) patients. Three (1.5%) patients were submitted to surgery. Steroid-free remission was achieved in 115 (59.3%) patients. Both serum C-Reactive Protein and Fecal Calprotectin (FC) levels were significantly reduced with respect to baseline levels during follow-up. A logistic regression, UST therapy as third-line therapy (after both anti-TNFα and vedolizumab), FC >200 µg/g, and HBI ≥8 were significantly associated with lack of remission. Adverse events occurred in 5 (2.6%) patients, and four of them required suspension of treatment. CONCLUSIONS: UST seemed to be really effective and safe in CD patients unresponsive to other biologic treatments, especially when used as second-line treatment.

Shape Changes in the Mirror Nuclei

We studied the proton-rich T_{z}=-1 nucleus ^{70}Kr through inelastic scattering at intermediate energies in order to extract the reduced transition probability, B(E2;0^{+}→2^{+}). Comparison with the other members of the A=70 isospin triplet, ^{70}Br and ^{70}Se, studied in the same experiment, shows a 3σ deviation from the expected linearity of the electromagnetic matrix elements as a function of T_{z}. At present, no established nuclear structure theory can describe this observed deviation quantitatively. This is the first violation of isospin symmetry at this level observed in the transition matrix elements. A heuristic approach may explain the anomaly by a shape change between the mirror nuclei ^{70}Kr and ^{70}Se contrary to the model predictions.

Water quality and human health: A simple monitoring model of toxic cyanobacteria growth in highly variable Mediterranean hot dry environments.

Due to population growth, urbanization and economic development, demand for freshwater in urban areas is increasing throughout Europe. At the same time, climate change, eutrophication and pollution are affecting the availability of water supplies. Sicily, a big island in southern Italy, suffers from an increasing drought and consequently water shortage. In the last decades, in Sicilian freshwater reservoirs several Microcystis aeruginosa and more recently Planktothrix rubescens blooms were reported. The aims of the study were: (1) identify and quantify the occurring species of cyanobacteria (CB), (2) identify which parameters, among those investigated in the waters, could favor their growth, (3) set up a model to identify reservoirs that need continuous monitoring due to the presences, current or prospected, of cyanobacterial blooms and of microcystins, relevant for environmental and, consequentially, for human health. Fifteen artificial reservoirs among the large set of Sicilian artificial water bodies were selected and examined for physicochemical and microbiological characterization. Additional parameters were assessed, including the presence, identification and count of the cyanobacterial occurring species, the measurement of microcystins (MCs) levels and the search for the genes responsible for the toxins production. Principal Component Analysis (PCA) was used to relate environmental condition to cyanobacterial growth. Water quality was poor for very few parameters, suggesting common anthropic pressures, and PCA highlighted clusters of reservoirs vulnerable to hydrological conditions, related to semi-arid Mediterranean climate and to the use of the reservoir. In summer, bloom was detected in only one reservoir and different species was highlighted among the Cyanobacteria community. The only toxins detected were microcystins, although always well below the WHO reference value for drinking waters (1.0 µg/L). However, molecular analysis could not show the presence of potential cyanotoxins producers since a few numbers of cells among total could be sufficient to produce these low MCs levels but not enough high to be proved by the traditional molecular method applied. A simple environmental risk-based model, which accounts for the high variability of both cyanobacteria growth and cyanotoxins producing, is proposed as a cost-effective tool to evaluate the need for monitoring activities in reservoirs aimed to guarantee supplying waters safety.

Publisher Correction: The observation of vibrating pear-shapes in radon nuclei.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Establishing the Maximum Collectivity in Highly Deformed N=Z Nuclei.

The lifetimes of the first excited 2^{+} states in the N=Z nuclei ^{80}Zr, ^{78}Y, and ^{76}Sr have been measured using the γ-ray line shape method following population via nucleon-knockout reactions from intermediate-energy rare-isotope beams. The extracted reduced electromagnetic transition strengths yield new information on where the collectivity is maximized and provide evidence for a significant, and as yet unexplained, odd-odd vs even-even staggering in the observed values. The experimental results are analyzed in the context of state-of-the-art nuclear density-functional model calculations.

Isospin Properties of Nuclear Pair Correlations from the Level Structure of the Self-Conjugate Nucleus

The low-lying energy spectrum of the extremely neutron-deficient self-conjugate (N=Z) nuclide _{44}^{88}Ru_{44} has been measured using the combination of the Advanced Gamma Tracking Array (AGATA) spectrometer, the NEDA and Neutron Wall neutron detector arrays, and the DIAMANT charged particle detector array. Excited states in ^{88}Ru were populated via the ^{54}Fe(^{36}Ar,2nγ)^{88}Ru^{*} fusion-evaporation reaction at the Grand Accélérateur National d'Ions Lourds (GANIL) accelerator complex. The observed γ-ray cascade is assigned to ^{88}Ru using clean prompt γ-γ-2-neutron coincidences in anticoincidence with the detection of charged particles, confirming and extending the previously assigned sequence of low-lying excited states. It is consistent with a moderately deformed rotating system exhibiting a band crossing at a rotational frequency that is significantly higher than standard theoretical predictions with isovector pairing, as well as observations in neighboring N>Z nuclides. The direct observation of such a "delayed" rotational alignment in a deformed N=Z nucleus is in agreement with theoretical predictions related to the presence of strong isoscalar neutron-proton pair correlations.

First Exploration of Neutron Shell Structure below Lead and beyond N=126.

The nuclei below lead but with more than 126 neutrons are crucial to an understanding of the astrophysical r process in producing nuclei heavier than A∼190. Despite their importance, the structure and properties of these nuclei remain experimentally untested as they are difficult to produce in nuclear reactions with stable beams. In a first exploration of the shell structure of this region, neutron excitations in ^{207}Hg have been probed using the neutron-adding (d,p) reaction in inverse kinematics. The radioactive beam of ^{206}Hg was delivered to the new ISOLDE Solenoidal Spectrometer at an energy above the Coulomb barrier. The spectroscopy of ^{207}Hg marks a first step in improving our understanding of the relevant structural properties of nuclei involved in a key part of the path of the r process.

Evolution of Octupole Deformation in Radium Nuclei from Coulomb Excitation of Radioactive

There is sparse direct experimental evidence that atomic nuclei can exhibit stable "pear" shapes arising from strong octupole correlations. In order to investigate the nature of octupole collectivity in radium isotopes, electric octupole (E3) matrix elements have been determined for transitions in ^{222,228}Ra nuclei using the method of sub-barrier, multistep Coulomb excitation. Beams of the radioactive radium isotopes were provided by the HIE-ISOLDE facility at CERN. The observed pattern of E3 matrix elements for different nuclear transitions is explained by describing ^{222}Ra as pear shaped with stable octupole deformation, while ^{228}Ra behaves like an octupole vibrator.

Estimating the association between antibiotic exposure and colonization with extended-spectrum ß-lactamase-producing Gram-negative bacteria using machine learning methods: a multicentre, prospective cohort study.

OBJECTIVES: The aim of the study was to measure the impact of antibiotic exposure on the acquisition of colonization with extended-spectrum ß-lactamase-producing Gram-negative bacteria (ESBL-GNB) accounting for individual- and group-level confounding using machine-learning methods. METHODS: Patients hospitalized between September 2010 and June 2013 at six medical and six surgical wards in Italy, Serbia and Romania were screened for ESBL-GNB at hospital admission, discharge, antibiotic start, and after 3, 7, 15 and 30 days. Primary outcomes were the incidence rate and predictive factors of new ESBL-GNB colonization. Random forest algorithm was used to rank antibiotics according to the risk of selection of ESBL-GNB colonization in patients not colonized before starting antibiotics. RESULTS: We screened 10 034 patients collecting 28 322 rectal swab samples. New ESBL-GNB colonization incidence with and without antibiotic treatment was 22/1000 and 9/1000 exposure-days, respectively. In the adjusted regression analyses, antibiotic exposure (hazard ratio (HR) 2.38; 95% CI 1.29-4.40), age 60-69 years (HR 1.19; 95% CI 1.05-1.34), and spring season (HR 1.25; 95% CI 1.14-1.38) were independently associated with new colonization. Monotherapy ranked higher als combination therapy in promoting ESBL-GNB colonization. Among monotherapy, cephalosporins ranked first followed by tetracycline (second), macrolide (fourth) and cotrimoxazole (seventh). Overall the ranking of cephalosporins was lower when used in combination. Among combinations not including cephalosporins, quinolones plus carbapenems ranked highest (eighth). Among sequential therapies, quinolones ranked highest (tenth) when prescribed within 30 days of therapy with cephalosporins. CONCLUSIONS: Impact of antibiotics on selecting ESBL-GNB at intestinal level varies if used in monotherapy or combination and according to previous antibiotic exposure. These finding should be explored in future clinical trials on antibiotic stewardship interventions. CLINICAL TRIAL REGISTRATION: NCT01208519.

Strain analysis reveals subtle systolic dysfunction in confirmed and suspected myocarditis with normal LVEF. A cardiac magnetic resonance study.

AIMS: Lake Louise Criteria (LLC) are time-dependent and some acute myocarditis (AM) with preserved left ventricular ejection fraction (LVEF) could be missed, due to the limited accessibility of Cardiac Magnetic Resonance (CMR). We aimed to assess the potential value of cardiac strain measured by feature tracking (FT) imaging in this population. METHODS AND RESULTS: Eighty-three patients with clinically suspected AM and normal LVEF were divided into 39 "confirmed AM" (positive LLC) and 44 "suspected AM" (negative LLC). An age and gender-matched sample of 42 normal subjects underwent CMR. In all groups, FT-derived biventricular strains and STE- global longitudinal strain (GLS) were assessed, being regularly measurable. Strain values < 5th percentile of the control group were considered abnormal. "Suspected" and "confirmed" AM were similar, except for medium time of CMR evaluation (5.2 vs 1 months from presentation, respectively; p = 0.004). Compared to healthy controls, both "suspected" and "confirmed" AM showed significantly impaired strain values. LV-global circumferential strain (GCS), right ventricular GCS and LV-GLS were abnormal in 15.4% and 15.9%, 20.5% and 15.9%, 7.7% and 9.1% in "confirmed" and "suspected" AM, respectively. STE analysis confirmed the results on LV-GLS, however a weak correlation emerged between STE and CMR-FT LV-GLS (p = 0.08). CONCLUSIONS: Compared to STE, CMR-FT analysis provided a more comprehensive and complementary biventricular strain evaluation that resulted similar in "confirmed" and "suspected" AM with normal LVEF. Conversely, mostly biventricular GCS was significantly reduced in up to 20% of patients, compared to healthy controls.

Rapid molecular tests for detection of antimicrobial resistance determinants in Gram-negative organisms from positive blood cultures: a systematic review and meta-analysis.

BACKGROUND: Timely detection of antimicrobial (cephalosporin/carbapenem) resistance (AMR) determinants is crucial to the clinical management of bloodstream infections caused by Gram-negative bacteria (GNB). OBJECTIVES: To review and meta-analyse the evidence for using commercially available molecular tests for the direct detection of AMR determinants in GNB-positive blood cultures (PBCs). DATA SOURCES: PubMed, Scopus and ISI Web of Knowledge. STUDY ELIGIBILITY CRITERIA: Clinical studies evaluating the performance of two major commercial systems, namely the Verigene® and FilmArray® systems, for rapid testing of GNB-PBCs, in comparison with the phenotypic or genotypic methods performed on GNB-PBC isolates. METHODS: Literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria and, for meta-analysis of sensitivity and specificity of both systems, bivariate random-effects model. RESULTS: Twenty studies were identified (3310 isolates) from 2006 to 2019. Nine studies were conducted in East Asia. In 15 studies using phenotypic comparators (1930 isolates), 1014 (52.5%) isolates were Escherichia coli, and 287 (14.9%) of all the isolates displayed AMR phenotypes. In five studies using genotypic comparators (1380 isolates), 585 (42.4%) were E. coli, and 100 (7.2%) of all the isolates displayed AMR genotypes. Pooled sensitivity and specificity estimates for detection of AMR determinants by the Verigene (i.e. CTX-M, IMP, KPC, NDM, OXA and VIM) and/or FilmArray (i.e. KPC) systems were 85.3% (95% CI 79.9%-89.4%) and 99.1% (95% CI 98.2%-99.5%), respectively, across the 15 studies, and 95.5% (95% CI 89.2%-98.2%) and 99.7% (95% CI 99.1%-99.9%), respectively, across the five studies. CONCLUSIONS: Our findings show that the Verigene and FilmArray systems may be a valid adjunct to the conventional microbiology (phenotypic or genotypic) methods used to identify AMR in GNBs. The FilmArray system detects only one AMR genotype, namely KPC, limiting its use. Both Verigene and FilmArray systems can miss important cephalosporin/carbapenem resistance phenotypes in a minority of cases. However, the sensitivity and specificity of both systems render them valuable clinical tools in timely identification of resistant isolates. Further studies will establish the prominence of such rapid diagnostics as standard of care in individuals with bloodstream infections.

The observation of vibrating pear-shapes in radon nuclei.

There is a large body of evidence that atomic nuclei can undergo octupole distortion and assume the shape of a pear. This phenomenon is important for measurements of electric-dipole moments of atoms, which would indicate CP violation and hence probe physics beyond the Standard Model of particle physics. Isotopes of both radon and radium have been identified as candidates for such measurements. Here, we observed the low-lying quantum states in 224Rn and 226Rn by accelerating beams of these radioactive nuclei. We show that radon isotopes undergo octupole vibrations but do not possess static pear-shapes in their ground states. We conclude that radon atoms provide less favourable conditions for the enhancement of a measurable atomic electric-dipole moment.

Pseudospin Symmetry and Microscopic Origin of Shape Coexistence in the

Lifetime measurements of excited states of the light N=52 isotones ^{88}Kr, ^{86}Se, and ^{84}Ge have been performed, using the recoil distance Doppler shift method and VAMOS and AGATA spectrometers for particle identification and gamma spectroscopy, respectively. The reduced electric quadrupole transition probabilities B(E2;2^{+}→0^{+}) and B(E2;4^{+}→2^{+}) were obtained for the first time for the hard-to-reach ^{84}Ge. While the B(E2;2^{+}→0^{+}) values of ^{88}Kr, ^{86}Se saturate the maximum quadrupole collectivity offered by the natural valence (3s, 2d, 1g_{7/2}, 1h_{11/2}) space of an inert ^{78}Ni core, the value obtained for ^{84}Ge largely exceeds it, suggesting that shape coexistence phenomena, previously reported at N≲49, extend beyond N=50. The onset of collectivity at Z=32 is understood as due to a pseudo-SU(3) organization of the proton single-particle sequence reflecting a clear manifestation of pseudospin symmetry. It is realized that the latter provides actually reliable guidance for understanding the observed proton and neutron single particle structure in the whole medium-mass region, from Ni to Sn, pointing towards the important role of the isovector-vector ρ field in shell-structure evolution.

Genetics of Dilated Cardiomyopathy: Clinical Implications.

PURPOSE OF REVIEW: This review aims to summarize the current knowledge on the genetic background of dilated cardiomyopathy (DCM), with particular attention to the genotype-phenotype correlations and the possible implications for clinical management. RECENT FINDINGS: Next generation sequencing (NGS) has led to the identification of an increasing number of genes and mutations responsible for DCM. This genetic variability is probably related to the extreme heterogeneity of disease manifestation. Important findings have associated mutations of Lamin A/C (LMNA) and Filamin C (FLNC) to poor prognosis and the propensity to cause an arrhythmic phenotype, respectively. However, a deeper understanding of the genotype-phenotype correlation is necessary, because it could have several implications for the clinical management of the patients. Furthermore, the correct interpretation of pathogenicity of mutations and the clinical impact of genetic testing in DCM patients still represent important fields to be implemented. A pathogenic gene mutation can be identified in almost 40% of DCM patients. The recent discoveries and future research in the field of genotype-phenotype correlation may lead to a more personalized management of the mutation carriers towards the application of precision medicine in DCM.

Shell Evolution towards

The level structure of the neutron-rich ^{77}Cu nucleus is investigated through ß-delayed γ-ray spectroscopy at the Radioactive Isotope Beam Factory of the RIKEN Nishina Center. Ions of ^{77}Ni are produced by in-flight fission, separated and identified in the BigRIPS fragment separator, and implanted in the WAS3ABi silicon detector array, surrounded by Ge cluster detectors of the EURICA array. A large number of excited states in ^{77}Cu are identified for the first time by correlating γ rays with the ß decay of ^{77}Ni, and a level scheme is constructed by utilizing their coincidence relationships. The good agreement between large-scale Monte Carlo shell model calculations and experimental results allows for the evaluation of the single-particle structure near ^{78}Ni and suggests a single-particle nature for both the 5/2_{1}^{-} and 3/2_{1}^{-} states in ^{77}Cu, leading to doubly magic ^{78}Ni.

_{36}

Prompt γ-ray spectroscopy of the neutron-rich ^{96}Kr, produced in transfer- and fusion-induced fission reactions, has been performed using the combination of the Advanced Gamma Tracking Array and the VAMOS++ spectrometer. A second excited state, assigned to J^{π}=4^{+}, is observed for the first time, and a previously reported level energy of the first 2^{+} excited state is confirmed. The measured energy ratio R_{4/2}=E(4^{+})/E(2^{+})=2.12(1) indicates that this nucleus does not show a well-developed collectivity contrary to that seen in heavier N=60 isotones. This new measurement highlights an abrupt transition of the degree of collectivity as a function of the proton number at Z=36, of similar amplitude to that observed at N=60 at higher Z values. A possible reason for this abrupt transition could be related to the insufficient proton excitations in the g_{9/2}, d_{5/2}, and s_{1/2} orbitals to generate strong quadrupole correlations or to the coexistence of competing different shapes. An unexpected continuous decrease of R_{4/2} as a function of the neutron number up to N=60 is also evidenced. This measurement establishes the Kr isotopic chain as the low-Z boundary of the island of deformation for N=60 isotones. A comparison with available theoretical predictions using different beyond mean-field approaches shows that these models fail to reproduce the abrupt transitions at N=60 and Z=36.

Public perception of dermatology and dermatologists in Italy: results from a population-based national survey.

INTRODUCTION: The public perception of dermatology and dermatologists may be very relevant in guiding strategies for improving dermatologic care but it has been poorly investigated in Europe. OBJECTIVE: To investigate the public's perception of dermatology and dermatologists in Italy. METHODS: A representative sampling of Italian adults (n = 1500, aged 18-70 years), residing throughout the national territory was interviewed through a population-based telephone survey using a structured questionnaire. RESULTS: The majority of interviewed aged between 35 and 54 years (45%) and had an intermediate educational level (57%), were employed (56%), and had at least one child in the family (68%). 70% of the interviewed knew at least one skin disease, particularly psoriasis, dermatitis, urticaria, skin tumours and nevi. The general practitioner resulted to be the first healthcare provider to consult in the case of skin problems for 73% of surveyed, with only 27% referring directly the private dermatologist. The dermatologist was the main referral specialist for psoriasis, pruritus and skin tumours by 66%, 54% and 53% of the sample, respectively. The most common reason for dermatological consultation was the control of nevi. In the case of childhood dermatitis, 52% indicated the paediatrician and 38% the dermatologist as the reference specialist. Almost half of the surveyed turned out to have a trusted dermatologist to consult in the case of skin problems. Finally, among those visited at least one time by a dermatologist, 46% were promoters, that is, they would recommend their dermatologist to a friend (net promoter score, 27). CONCLUSIONS: The general population has a wide-ranging understanding of skin diseases and the central role of dermatologists in skin care. Patients are looking for technical competence and loyalty, because this lead to more trusted and satisfactory physician-patient relationship. Public campaigns may be relevant in increasing awareness on curability of common skin diseases.